Vicriviroc: long-term safety concerns over cancers dispelled

In an analysis of 192 weeks of vicriviroc use, with a mean duration of 96 weeks use in 205 treatment-experienced patients, toxicities were reported to appear "infrequently and sporadically", with no specific toxicities clearly related to vicriviroc use. In particular, incidence of cancers (some cases of which caused concern in earlier studies) did not increase over time. The results were reported in a poster presentation to the 48^th Interscience Conference on Antimicrobial Agents and Chemotherapy in Washington DC this week.

Vicriviroc (VCV) is a CCR5 inhibitor being developed by Schering-Plough. Previous reports have shown vicriviroc to have potent activity against HIV in treatment-experienced people when added to an antiretroviral (ART) regimen containing ritonavir-boosted protease inhibitors. While these earlier reports have cited "no clinically relevant safety differences" compared to placebo, side-effects and toxicities have not been reported in great detail.

Also, cases of cancer have been reported in trial participants, and while these are thought not to be drug-related, the association had not yet been definitively ruled out.

This report was based on pooled data from participants in studies A5211 and VICTOR-E1, who received open-label vicriviroc after completing 48 weeks in the trials. Doses originally ranged from 5 to 30mg, but were all escalated to 30mg once daily as that dose was found most effective.

For the 205 participants in the two trials, the mean duration of treatment was 80 weeks, and 196 received at least 12 weeks of vicriviroc. Participants had fairly advanced HIV disease, with a mean CD4 cell count of 201 cells/mm³ and a median of 162 cells/mm³ at study entry, and prior AIDS-defining events in 52%.

The analysis specifically looked at AIDS complications, malignancies (cancers), infections and liver-related abnormalities, as well as viral load levels and CD4 cell counts. Comparable rates of these adverse events for patients not on vicriviroc were not provided. The following adverse events were seen in the 205 participants:

• Fourteen cases of AIDS complications, including: nine opportunistic infections (OIs), two cases of Kaposi's sarcoma (KS), two of wasting syndrome and one case of PML.
• Liver abnormalities included one case of cirrhosis, one of hepatosplenomegaly (enlarged liver and spleen), 14 elevated ALT levels, 17 elevated AST levels, and 25 elevated bilirubin levels. AST/ALT elevations were generally mild and not deemed drug related. All cases of high bilirubin were in people taking atazanavir (without AST/ALT elevation).
• The most common infections (reported in at least 5% of participants) included sinusitis (11%), upper respiratory infections (9%), bronchitis (9%), herpes simplex (6%), influenza (5%) and pneumonia (5%).
• Thirteen malignancies were reported: seven cases of skin cancer (this included the two KS cases), five lymphomas, and one gastric carcinoma. The incidence rate of malignancies remained nearly constant over time rather than increasing as the cumulative exposure to vicriviroc increased, suggesting that vicriviroc treatment "likely does not increase the already elevated risk of developing malignancy in this study population."

The investigators concluded that the data from these subjects, representing "the longest clinical experience and treatment duration with a CCR5 antagonist reported to date", showed that vicriviroc "demonstrated excellent tolerability, and is not associated with hepatotoxicity, seizures, or ischemic cardiovascular events." A 30mg dose of vicriviroc is now being studied in Phase III trials.